Treatment of highly vascular tumors

ABSTRACT

A method of treating a patient having a highly vascular tumor includes administering a therapeutically effective amount of dextrin sulphate to the patient. The highly vascular tumor can be, for example, Kaposi&#39;s sarcoma. The treatment results in regression of the tumors and the improvement persists for a considerable time after completion of the treatment.

This invention relates to the treatment of patients suffering fromhighly vascular tumours. Such tumours have extensive new formation ofwell formed and poorly formed blood vessels, with numerous capillariesand larger channels which are composed mainly of a layer of endotheliumsupported by cells of different types (e.g. small spindle cells, plasmacells, lymphocytes) which can in themselves be abnormal.

The invention is particularly concerned with a condition known asKaposi's Sarcoma. A sarcoma is a malignant tumour of connective tissueof mesenchymal origin. The condition known as Kaposi's Sarcoma (KS) is amultifocal, reactive, vascular proliferation which can, in time, acquiresome of the features associated with a malignant tumour. KS is usuallyseen in immunosuppressed patients and occurs in several distinctclinical forms, which include:

(i) Sporadic (classic) KS. This was the first form of KS to be observed.It was seen many years ago (by Kaposi) in Jewish communities in EasternEurope.

(ii) Endemic (African) KS. This occurs in sub-Saharan Africa.

(III) Epidemic (AIDS) KS. This occurs in AIDS patients.

(iv) Iatrogenic KS. This occurs mainly in transplant patients who havebeen given immunosuppressive medication.

As yet, it has not been possible to establish clear biological orhistopathological differences which would serve to explain thesedifferent clinical and pathological forms of KS.

The evolution of both skin and lymphadenopathic KS from earlyangiomatous lesions to the patch and nodular stages of KS ischaracterised by a progressive increase in the number of spindle cells.The highly vascular nature of this tumour may suggest that it developsfrom aberrant lymphatico-venous connections which, in early macularlesions, are lined by cells which are phenotypically similar tolymphatic epithelium. However, questions remain about the histocytogenicorigin of the spindle cells and the pathogenic factors which drive theproliferation of these cells during the evolution of KS. These questionsrevolve around whether the KS lesion constitutes clonal malignantproliferation or a hyperproliferative “reactive” response to an unknownstimulus or stimuli. It is possible that the mixed cell proliferation isproduced by a minority of tumour cells which have constitutive geneticabnormalities or aneuploidy.

The heterogeneity of proliferating cells in a KS lesion suggests acomplex network of cell stimulation. In the case of KS-derived spindlecells which have been cultured in vitro, several cytokines withautocrine and paracrine growth properties (e.g. beta-FGF, IL-1, GM-CSF,platelet derived growth factor, and oncostatin-M) have been shown toinduce local angiogenesis in the skin of nude mice and in achorioallantoic membrane assay.

In the current clinical approaches to the treatment of KS it has beenfound that early skin lesions respond to radiotherapy. More severe,disseminated disease requires treatment with cytotoxic chemotherapeuticagents such as doxorubicin, vincristine and bleomycin which have to beadministered intravenously. These treatment regimens are oftenassociated with severe clinical toxicity in patients who are alreadydebilitated and immunosuppressed. One of the most common reasons forinterrupting cycles of chemotherapy during a course of treatment of KSwith anthracycline drugs (e.g. adriamycin) is neutropenia. Morerecently, administration of liposomal preparations of daunorubicin anddoxorubicin has also resulted in the rapid regression of KS lesions. Forthose KS lesions which are seen in patients on iatrogenicimmunosuppression the tumour regresses when the degree ofimmunosuppression is reduced.

The number of cases of AIDS-related cases of KS has increaseddramatically in recent years. It has been postulated that KS spindlecell growth in vitro and in vivo may be modulated by HIV-1. However,both immunohistochemistry for HIV-1 proteins as well as PCR for HIV-1DNA have failed to find any evidence that HIV-1 is present in thespindle cell population of epidemic KS lesions. Moreover, treatment ofKS lesions with drugs known to reduce the viral load of HIV-1 in theblood substantially, such as zidovudine (AZT), didanosine (ddI) and/orzalcitabine (ddC), does not result in the regression or the healing ofKS lesions. Thus, it seems that KS is not caused simply by the presenceof HIV-1, particularly since KS can appear in patients who display nosign of this virus. Evidently, therefore, the fact that a drug is knownto have anti-HIV activity is not an indication that it is of value forthe treatment of KS.

We have found that administration of dextrin sulphate to patients havinghighly vascular tumours, in particular KS lesions, results in regressionof the tumours.

The present invention provides a method of treatment of a patient havinga highly vascular tumour, especially KS, which comprises administeringdextrin sulphate to the patient.

Dextrin sulphates are known compounds. They are produced by sulphationof dextrins, which are mixtures of glucose polymers produced byhydrolysis of starch. These glucose polymers have a wide range ofpolymerisation. The degree of polymerisation (D.P.) varies from 1 (themonomer, glucose) up to very high values, for example up to a hundredthousand or more glucose units.

Typically, the direct result of hydrolysing a starch is a dextrincontaining a high proportion of polymers of relatively low molecularweight and might for example contain up to 60% by weight of glucosepolymers of D.P. less than 12. The dextrin sulphates used in the presentinvention can have a wide range of composition, but are preferablyderived from dextrins containing at least 50% by weight, preferably morethan 90%, of glucose polymers greater than 12, and/or containing lessthan 10%, preferably less than 5%, by weight of glucose polymers of D.P.less than 12. The weight average molecular weight of the dextrin may,for example, be from 10,000 to 35,000, preferably 15,0000 to 25,000.(The technique used to determine the molecular weight of the dextrin ishigh-pressure liquid chromatography using chromatographic columnscalibrated with dextran standards, as designated by Alsop et al., J.Chromatography 246, 227-240, 1989). Preferably, the dextrin contains notmore than 10%, preferably less than 5%, by weight of polymers ofmolecular weight greater than 40,000. The desired weight averagemolecular weight and polymer profile is achieved by subjecting a dextrinto fractionation, using known techniques, including solventprecipitation and membrane fractionation. Among the dextrins from whichthe dextrin sulphates suitable for use in the present invention can bederived are those described in European patent specifications Nos.115911, 153164, and 207676.

Dextrin sulphates have been previously used pharmaceutically. Forexanple, British patent specification 871,590 discloses the use ofcertain dextrin sulphates as antilipaemic agents, and U.S. Pat. No.5,439,892 the use of certain dextrin sulphates as anti-HIV agents. Thesereferences also describe processes for the production of dextrinsulphates; their disclosures are incorporated herein by reference.

The Scandinavian Journal of Immunology, Volume 29 (2) pp 181-92, 1989discloses tumour regression after treatment with aminated β1-3Dpolyglucose.

In the method of the invention the dextrin sulphate can be administeredto the patient by any route, enteral or parenteral, at the discretion ofthe clinician. Intraperitoneal administration is particularly effective,but the dextrin sulphate can, for example, also be given orally,intravenously, or can be directly injected into the lesions of thetumour on a lesion by lesion basis, or can be topically applied. Thedosage level is to be determined by the clinician.

Dextrins can be sulphated in the 2, 3, and 6 positions, and a fullysulphated dextrin therefore contains three sulphate groups per glucoseunit. The dextrin sulphate used in the present invention may have anydegree of sulphation, but preferably it contains at most two, morepreferably from 0.5 to 1.5, sulphate groups per glucose unit. Also, thedextrin sulphate is preferably dextrin-2-sulphate, dextrin-6-sulphate ora mixture thereof.

The following example is given by way of illustration or the invention.

EXAMPLE

A composition for use in administering dextrin sulphateintraperitoneally was prepared, in the form of a sterile aqueoussolution containing:

Dextrin sulphate 100 micrograms/ml Glucose polymer mixture 10grams/liter Na 132 mmol/liter Ca 1.75 mmol/liter Mg 0.75 mmol/literLactate 35 mmol/liter

The dextrin sulphate was dextrin-2-sulphate, prepared as described inExample 3 of U.S. Pat. No. 5,439,892. The glucose polymer mixture,present in the solution as an osmotic agent, was the glucose polymermixture described in Example 2 of European specification 153164; itcontained 91.9% of polymers of D.P. greater than 12 and 7.9% of polymersof from D.P. 2 to 10, and had a weight average molecular weight of23,700.

The above solution was administered intraperitoneally to three patientswith multifocal, widely disseminated KS and having late stage AIDS. 1.5liters of the solution was introduced daily into the peritoneal cavityof the patient by way of indwelling catheter. The solution was allowedto remain in the peritoneal cavity for twenty-four hours and thenreplaced by fresh solution. This treatment was continued for thirtydays.

Regression of KS Lesions was observed. This response to the treatmentwas seen both on the skin and for those lesions which were on mucousmembranes (i.e. within the mouth). The response was slow and occurredover a period of months even though the period of treatment was only 30days. The improvement in the condition of the patient, who did notreceive further treatment, persisted for a considerable time.

There are, as yet, no formally accepted staging criteria for KS.However, the improvement in the patient's condition was assessed inaccordance with guidelines issued by the AIDS Clinical Trials GroupOncology Committee, which suggests the following criteria:

(a) Nodular lesions become flat.

(b) Lesions become darker in colour (i.e. mauve).

(c) The epithelium desquamates.

(d) Tumour-associated oedema resolves.

(e) Lymphoedema resolves

(f) Healed lesions develop a brown/tan halo.

(g) Previously ulcerated areas of large KS lesions which are notamenable to any other form of current therapy have healed.

In the case of the three patients treated as described above the processof healing was slow and took months rather than weeks. During the latterphase of the healing process of lesions which were present before thestart of administration of dextrin sulphate, some new lesions were seento arise. They were however morphologically quite distinct from thoseseen before the treatment in that they were very small (being measurablein millimeters rather than in centimeters), pink, and flat. Also, theygrew very slowly and were sometimes associated with a small number ofsatellite lesions. This is a very unusual presentation of KS in patientswith late stage AIDS.

In the above Example the dextrin sulphate was given to the patients in acarrier solution which was removed from the peritoneal cavity of thepatients and replaced by fresh solution on a daily basis. Othertreatment regimens, also using intraperitoneal administration arefeasible. if the carrier solution is left within the peritoneal cavity,and not removed therefrom, it is cleared by the body from the peritonealcavity, mainly into the lymphatic circulation. Full clearance is usuallyeffected in about forty-eight hours. Accordingly it is possible to usetreatment regimens in which the step of removing carrier liquid from thepatient is omitted; for example, (a) the dextrin sulphate may beadministered daily in a volume of carrier liquid comparable with thedaily clearance volume, or (b) the dextrin sulphate may be given to thepatient less often than daily, perhaps two or three times a week,depending on the clearance rate.

As the aetiology and pathogenesis of KS is not understood, the mechanismof action of dextrin sulphate on KS lesions is not yet known. The idealtreatment regimen therefore still remains to be determined and may ofcourse vary from patient to patient. However, as is evident from theabove Example, the dextrin sulphate does not have to be presentcontinuously for the KS to show improvement. It may therefore beappropriate for some patients to be given dextrin sulphate lessfrequently than on a daily basis, perhaps once a week.

What is claimed is:
 1. A method of treating a patient having a highlyvascular tumour which comprises administering a therapeuticallyeffective amount of dextrin sulphate to the patient.
 2. The method ofclaim 1 wherein said highly vascular tumour is Kaposi's sarcoma.
 3. Themethod of claim 1 wherein the dextrin sulphate is administered to thepatient intraperitoneally.
 4. The method of claim 1 wherein the dextrinsulphate is derived from a dextrin having at least 50% by weight ofglucose polymers of D.P. greater than
 12. 5. The method of claim 1wherein the dextrin sulphate is derived from a dextrin having more than90% by weight of glucose polymers of D.P. greater than
 12. 6. The methodof claim 1 wherein the dextrin sulphate is derived from a dextrincontaining less than 10% by weight of glucose polymers of D.P. less than12.
 7. The method of claim 1 wherein the dextrin sulphate is derivedfrom a dextrin containing less than 5% by weight of glucose polymers ofD.P. less than
 12. 8. The method of claim 1 wherein the dextrin sulphateis derived from a dextrin having a weight average molecular weight offrom 10,000 to 35,000.
 9. The method of claim 1 wherein the dextrinsulphate is derived from a dextrin containing less than 10% by weight ofglucose polymers of molecular weight greater than 40,000.
 10. The methodof claim 1 wherein the dextrin sulphate is derived from a dextrincontaining less than 5% by weight of glucose polymers of molecularweight greater than 40,000.
 11. The method of claim 1 wherein thedextrin sulphate contains at most two sulphate groups per glucose unit.12. The method of claim 1 wherein the dextrin sulphate contains between0.5 and 1.5 sulphate groups per glucose unit.
 13. The method of claim 1wherein the dextrin sulphate is dextrin-2-sulphate or dextrin-6-sulphateor a mixture thereof.
 14. The method of claim 1 wherein the dextrinsulphate is derived from a dextrin having a weight average molecularweight of from 15,000 to 25,000.